Evaluation of in vivo staging of amyloid deposition in cognitively unimpaired elderly aged 78-94.

Amyloid-beta (Aß) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aß. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aß deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aß, thus, it remains an open topic what constitutes abnormal brain Aß in the oldest-old and what is the best method to determine that.

Changes in the metabolic profiles of the serum and putamen in Parkinson's disease patients - In vitro and in vivo NMR spectroscopy studies.

The aim of this study was to investigate the relationship between serum metabolomic biomarkers and brain in vivo magnetic resonance spectroscopy (MRS) biomarkers in patients with Parkinson's disease (PD) as well as to investigate compound concentration changes by comparing the results with healthy control subjects. Univariate statistical analysis of the serum showed significant differences in the levels of phenylalanine, tyrosine, lysine, glutamine, glutamate, acetone, acetate, 3-hydroxybutyrate, and 1-monoacylglycerol (1-MAG) between the PD patient group and the control group. Orthogonal partial least squares discriminant analysis showed significantly different compound concentrations of acetate, 3-hydroxybutyrate, glutamine, tyrosine, 1-MAG and testosterone. In vivo MRS of the putamen showed significantly higher concentrations of glutamine/glutamate complex and glutamine in patients with PD in comparison to control subjects. Following disrupted metabolic pathways in patients with PD were identified: dopamine synthesis, steroid hormone biosynthesis, fatty acid biosynthesis, the synthesis and degradation of ketone bodies, the metabolism of pyruvate, arginine, proline, alanine, aspartate, glutamate, tyrosine and phenylalanine. The obtained results may indicate changes in neurotransmission, disturbances in energy production and an altered cell membrane structure.

Gene polymorphisms and motor levodopa-induced complications in Parkinson's disease.

OBJECTIVE: The aim of the study was to evaluate the association of individual and combined single-nucleotide polymorphisms in brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT) genes with the occurrence of motor levodopa-induced complications (MLIC) in Parkinson's disease (PD). MATERIALS AND METHODS: We studied 76 patients with PD (MLIC occurred in 56.6%) and 60 controls. Allelic discrimination of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes were genotyped. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multinominal logistic regression. Orthogonal partial least squares (OPLS) analysis and OPLS discriminant analysis (OPLS-DA) were used to analyze qualitative genetic data. RESULTS: The risk of PD in subjects with the AG BDNF genotype was increased sixfold (OR = 6.12, 95% CI = 2.88-13.02, p < .0001), and AG BDNF and AG DAT genotypes were correlated with PD in OPLS-DA (VIP > 1). There were no differences in distributions of BDNF, DAT and COMT genotypes between PD groups with and without MLIC, while OPLS model showed that genotype combination of AG BDNF, AG DAT, and GG COMT was correlated with MLIC and genotypes combination of GG BDNF, AA DAT, and AA COMT with lack of MLIC in PD patients (VIP > 1). CONCLUSIONS: Our results confirmed the association of rs6265 BDNF (Val66Met) with the risk of PD and suggest a synergic effect of rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) polymorphisms on the occurrence of MLIC.

Aryl hydrocarbon receptor (AhR) and its endogenous agonist - indoxyl sulfate in chronic kidney disease.

The indoxyl sulfate (IS, indoxyl sulphate) is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-ß and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR). This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciazethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.

Deep brain stimulation failure due to external cardioversion in a patient with Parkinson's disease.

We report a case of deep brain stimulation (DBS) hardware failure due to emergently performed subcutaneous coronary angioplasties complicated by cardioversion for rapid worsening of angina pectoris and some trouble shooting problems emerged after invasive cardiovascular procedures. The patient with prior implantation of permanent pacemaker due to vasovagal syndrome underwent successful left-sided unilateral electrode implantation into the subthalamic nucleus. During 21 months follow-up period the patient experienced 2 times episodes of aggravation of unstable angina pectoris 15 and 21 months respectively, which necessities emergent coronary angioplasties. After the first emergently performed coronary angioplasty with cardioversion the interrogation of DBS system revealed the depletion of an internal pulse generator (IPG). The secondly performed coronary angioplasty complicated by ventricular tachyarrhythmia with DBS system switched on during emergent cardioversion resulted in partial dysfunction of DBS electrode. Patients harboring cardiovascular implantable electronic devices (CIEDs) and DBS systems require special attention and good cooperation of neurosurgeons, interventional cardiologist, and neurologist. Some emergently performed invasive cardiovascular procedures which necessities cardioversion may cause DBS hardware failure with subsequent worsening of movement disorder symptoms.

Does the OPG/RANKL system contribute to the bone-vascular axis in chronic kidney disease? A systematic review.

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and is strongly associated with cardiovascular mortality and morbidity. Accumulating evidence over the past decade has challenged the hypothesis of close interaction between bone and VC what raises the possibility of a common underlying pathophysiological mechanism. Lately, bone regulatory proteins such as: osteoprotegerin (OPG) and Receptor Activator for Nuclear Factor κB Ligand (RANKL) has attracted attention of researchers as a possible key mediators of bone-vascular calcification imbalance. The literature search was carried out using the MEDLINE/PubMed database and a combination of keywords and MeSH terms, and only papers published since January 2005 to July 2016 were selected. The search resulted in 562 potential articles. After selection according to the eligibility criteria, 107 studies fulfilled were included (102 full texts and 5 was case reports). OPG and RANKL plays essential role in the regulation of bone metabolism and may be regarded as a possible link between VC, bone and mineral metabolism in CKD patients. Further studies are required to determine the diagnostic significance of these proteins in evaluation of progression and severity of VC process in CKD patients. Finally, the efficacy and safety, especially in regard to VC, of anti-RANKL therapy in CKD patients requires well-designed prospective, randomized trials.

Search for new potential anticonvulsants with anxiolytic and antidepressant properties among derivatives of 4,4-diphenylpyrrolidin-2-one.

BACKGROUND: The aim of this study was to synthesize a series of new N-Mannich bases derived from 4,4-diphenylpyrrolidin-2-one having differently substituted 4-phenylpiperazines as potential anticonvulsant agents with additional (beneficial) pharmacological properties. METHODS: The target compounds 8-12 were prepared in one step from the 4-substituted phenylpiperazines, paraformaldehyde, and synthesized 4,4-diphenylpyrrolodin-2-one (7) by a Mannich-type reaction. The obtained compounds were assessed and tested for their anticonvulsant activity in two screening mouse models of seizures, i.e., the maximal electroshock (MES) test and in the subcutaneous pentylenetetrazole (scPTZ) test. The effect of these compounds on animals' motor coordination was measured in the rotarod test. A selected 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) was evaluated in vivo for its anxiolytic- and antidepressant-like properties. Its impact on animals' locomotor activity was also evaluated. RESULTS: Compound 8 showed protection (25%) in the MES and in the scPTZ tests at the dose of 100mg/kg and was not neurotoxic. In the four-plate test, compound 8 at the dose of 30mg/kg showed a statistically significant (p<0.05) anxiolytic-like activity. In the forced swim test, it reduced the immobility time by 24.3% (significant at p<0.05), which indicates its potential antidepressant-like properties. In the locomotor activity test, compound 8 significantly reduced animals' locomotor activity by 79.9%. CONCLUSION: The results obtained make a new derivative of 4,4-diphenyl-1-((4-phenylpiperazin-1-yl)methyl)pyrrolidin-2-one (8) a promising lead structure for further development.

[Motor levodopa-induced complications in Parkinson's disease]. / Zaburzenia ruchowe po lewodopie u osób z choroba Parkinsona.

UNLABELLED: Chronic treatment with levodopa in Parkinson's disease (PD) is associated with the risk of development of motor fluctuations and dyskinesias, i.e. motor levodopa-induced complications (MLIC). AIM: The aim of the study was to investigate factors influencing prevalence of MLIC in PD patients. MATERIALS AND METHODS: 76 patients with idiopathic PD were included in the study. Theirs mean disease duration was 10,33 years and mean levodopa therapy duration was 8,65 years. The most common drug regimen was levodopa with ropinirole. The patients were evaluated using Hoehn and Yahr scale, UPDRS II, III, and were qualified for 4 clinical subtypes according to van Rooden at al. classification. RESULTS AND CONCLUSIONS: The prevalence of MLIC was 54% with their mean duration of 3,34 years. MLIC were influenced by higher levodopa equivalent dose, younger age at onset, younger age, longer disease duration, and longer levodopa therapy regardless of PD clinical subtype. Although women had more advanced disease according to Hoehn and Yahr score, sex did not influence MLIC. The incidence of MLIC in both sexes was probably leveled by inclusion of sex as a risk factor of MLIC in treatment strategy. Therefore modifiable MLIC risk factors should be investigated in different PD populations.

The Biomechanical Testing for the Assessment of Bone Quality in an Experimental Model of Chronic Kidney Disease.

Mineral metabolism disturbances are common in chronic kidney disease (CKD) and have been classified as a new clinical entity, also known as CKD-mineral and bone disorders (CKD-MBD). A decrease in the bone strength, whose clinical manifestation is a tendency for fracture, has been recognized as an important component of CKD-MBD. Because of ethical issues, measurements of the bone strength in the human body are usually limited to noninvasive techniques, such as radiography, dual-energy X-ray absorptiometry and the assays of bone turnover biomarkers. However, it has been postulated recently that the evidence concerning bone strength based solely on the determination of the bone quantity may be insufficient and that bone quality should also be examined. In this regard, an animal model of CKD can represent an experimental tool to test the effectiveness of new therapeutic strategies. Despite the many available methods that are used to diagnose metabolic bone disorders and predict fracture risk especially in small rodents with CKD, it turns out that the most appropriate are biomechanical tests, which can provide information about the structural and material properties of bone. The present review summarizes and discusses the principles for carrying out selected biomechanical tests (3-point bending test and compression test) and their application in clinical practice.

[Essential tremor and parkinsonian tremor long-term monitoring]. / Wielogodzinne monitorowanie drzenia samoistnego i drzenia parkinsonowskiego.

Instrumental methods of tremor investigation can be used in differential diagnosis between essential and parkinsonian tremor in uncertain cases. This paper describes the method of tremor quantification using long-term surface electro- myography registration of antagonistic forearm muscles. Examples of clinical application of the method are also given.

Falls in Parkinson's disease. Causes and impact on patients' quality of life.

The aim of this study was to investigate the prevalence of the different causes of falling in Parkinson's disease (PD) and to evaluate the influence of falls on patients' quality of life (QoL). We recruited 60 PD patients (31 with falls, 29 without falls). We found that falls were caused by: unstable posture (29.0%), freezing or festination (25.8%), sudden loss of postural reflexes (toppling falls) (25.8%), co-existing neurological disorders (6.5%), cardiological disorders (6.5%), and symptomatic orthostatic hypotension (3.2%). Duration of the disease was longer, its stage more advanced, daily levodopa dosage higher, and the proportion of patients with abnormalities in the EEG apparently greater in the group with falls. The presence of falls was found to be a factor contributing to a multidirectional negative impact on patients' QoL. QoL also depended on impairment of cognitive function, daily dosage of levodopa, disease duration, disease progression, and sex. The results of this study underline the need to diagnose the causes of falls in order to institute appropriate treatment and to improve patients' QoL.

[Frequency of Bordetella pertussis antibodies in serum of patients with Parkinson's disease]. / Czestosc wystepowania surowiczych przeciwcial przeciwko paleczce krztusca w chorobie Parkinsona.

The assessment of the levels of IgG antibodies against Bordetella pertussis in serum using ELISA test was performed in 59 patients (including 30 patients with Parkinson's disease--PD, 15 patients with other non-inflammatory neurological diseases, and 14 controls). The average age in the groups was 64.0, 64.4, and 58.7 years, respectively. Positive results were found in 17/30 patients with PD, 8/15 subjects with other non-inflammatory neurological diseases and in 7/14 controls. The above results are surprising and demonstrate a high incidence of subclinical whooping cough among the adult population. No statistically significant difference has been found between patients with Parkinson's disease and patients with other neurological diseases. A tendency is observed for a higher percentage of negative results among controls in comparison with patients with Parkinson's disease and other non-inflammatory neurological diseases.

[Analysis of causes for falls in people with Parkinson's disease]. / Analiza przyczyn upadków u osób z choroba Parkinsona.

Falls in Parkinson's disease may pose a significant threat for patients. This is not only a clinical problem, but also an economic one. The effects of falls may cause deterioration of the quality of life for both patients and their caretakers. The causes of falls are not clinically uniform: the falls are caused by various factors and require a differential diagnosis. The purpose of this paper is to analyse the above mentioned causes, as well as to draw clinicians' attention to the possibility of effective therapy for certain disorders that cause such falls in patients with Parkinson's disease. 51 patients with recognized Parkinson's disease were examined, including 25 persons who reported falls that had occurred within the past 6 months and 26 persons who had no falls. In both groups there were patients with different types of the disease (tremulous, akinetic-hipertonic and mixed). The clinical status of the patients was assessed using the Hoehn and Yahr scale. In each patient Schellong test and EEG examinations were performed. It has been established that the occurrence of falls is related to the duration of the disease (on average 9.6 years in the group with falls versus 6.2 years in the group without falls) and the daily levodopa dosage (on average 806.0 mg in the group with falls versus 499.0 mg in the group without falls). The proportion of patients with abnormalities in the EEG (revealed mainly as slowing of EEG background activity) was notably higher in the group with falls. The comparison of such groups from the point of view of sex, age, stage of the disease and the occurrence of asymptomatic orthostatic hypotension did not reveal any statistically significant differences. The analysis of the causes of falls in the examined patients revealed that in 8 cases they fell due to unstable posture, 4--due to freezing or festination, 1--due to symptomatic orthostatic hypotension, 1--due to co-existing neurological disorders, 2--due to the heart arrhythmia (requiring implantation of pacemaker), in 8 persons--due to toppling falls and in 1 patients the falls could not be classified.